Process for Preparing Microcrystals

Abstract

This invention relates in general to micron or sub-micron particles comprising one or more water-soluble crystals wherein the crystals have a surface coating comprising one or more bioactive molecules as well as efficient methods of forming such particles and rapid methods for screening preferred conditions to form such particles. The particles are suitable for pharmaceutical formulations.

1 . A continuous method of forming bioactive molecule coated microcrystals comprising the following steps:
 (a) providing a first aqueous solution comprising coprecipitant molecules;   (b) providing a second aqueous solution comprising bioactive molecules;   (c) providing a third solution comprising water miscible solvent;   (d) either
 i) mixing said first aqueous solution, said second aqueous solution and said third solution substantially simultaneously; or 
 ii) mixing either the first and second aqueous solutions with the third solution and thereafter mixing with the remaining of either the first and second aqueous solutions; such that coprecipitation of the coprecipitant and the bioactive molecules is initiated, leading to formation of said microcrystals; and 
   (e) collecting a suspension of microcrystals.   
     
     
         2 . A method according to  claim 1 , wherein the water miscible solvents are selected from short-chain alcohols; aldehydes, ketones, esters, ethers, diols, various size polyethylene glycol (PEGS), polyols; and combinations or mixtures thereof. 
     
     
         3 . A method according to  claim 2 , wherein the short chain alcohol is methanol, ethanol, propan-1-ol, or propan-2-ol, the ketone is acetone, the ester is ethyl lactate, the ether is tetrahydrofuran, or the diol is 2-methyl-2,4-pentanediol or 1,5-pentane diol. 
     
     
         4 . A method according to  claim 1 , wherein a first pump continuously delivers the first aqueous solution comprising coprecipitant molecules, a second pump continuously delivers the second aqueous solution comprising bioactive molecules and a third pump continuously delivers the third solution comprising water miscible solvent. 
     
     
         5 . A method according to  claim 1 , wherein a first pump continuously delivers either the first and second aqueous solutions to the third solution which is continuously delivered by a second pump, with a third pump thereafter continuously delivering the remaining of either the first and second aqueous solutions. 
     
     
         6 . A method according to  claim 1 , wherein the aqueous solutions are delivered at flow rates between about 0.2 ml/min and about 1000 ml/min. 
     
     
         7 . A pharmaceutical formulation comprising particles that contain one or more microcrystals, wherein the microcrystals comprise:
 (a) a substantially non-hygroscopic inner crystalline core formed from coprecipitant molecules; and   (b) an outer coating comprising one or more bioactive molecules;   wherein the coated microcrystals have been formed in a single continuous process comprising the steps of   a) substantially mixing a first aqueous solution comprising coprecipitant molecules, a second solution comprising bioactive molecules, and a third solution comprising water miscible solvent; or   b) mixing either the first and second aqueous solutions with the third solution and thereafter mixing with the remaining of either the first and second aqueous solution.   
     
     
         8 . A pharmaceutical formulation according to  claim 7 , wherein the outer coating thickness ranges from about 0.01 to about 1000 microns. 
     
     
         9 . A pharmaceutical formulation according to  claim 7 , wherein the outer coating thickness ranges from about 1 to about 100 microns. 
     
     
         10 . A pharmaceutical formulation according to  claim 7 , wherein the outer coating thickness ranges from about 5 to about 50 microns. 
     
     
         11 . A pharmaceutical formulation according to  claim 7 , wherein the outer coating thickness ranges from about 10 to about 20 microns. 
     
     
         12 . A pharmaceutical formulation according to  claim 7 , wherein the particles have a maximum cross-sectional dimension of less than about 80 μm. 
     
     
         13 . A pharmaceutical formulation according to  claim 7 , wherein the particles have a maximum cross-sectional dimension of less than about 50 μm across. 
     
     
         14 . A pharmaceutical formulation according to  claim 7 , wherein the particles have a maximum cross-sectional dimension of less than about 20 μm. 
     
     
         15 . A pharmaceutical formulation according to  claim 7 , wherein the molecules making up the crystalline core have a molecular weight less than about 2 kDa. 
     
     
         16 . A pharmaceutical formulation according to  claim 7 , wherein the molecules which make up the crystalline core are selected from amino acids, zwitterions, peptides, sugars, buffer components, water soluble drugs, organic and inorganic salts, compounds that form strongly hydrogen bonded lattices and derivatives or combinations thereof. 
     
     
         17 . A pharmaceutical formulation according to  claim 7 , comprising one or more drugs selected from anti-inflammatories; anti-cancer; anti-psychotic; anti-bacterial; anti-fungal; natural or unnatural peptides; proteins such as insulin, α1-antitrypsin, α-chymotrypsin, albumin; interferons; antibodies; fusion proteins such as Fc-fusion proteins; protein-drug conjugates, nucleic acids such as fragments of genes, DNA, RNA or RNAi from natural sources or synthetic oligonucleotides and anti-sense nucleotides; mono-saccharides, di-saccharides, polysaccharides; plasmids; and protein/peptide-drug conjugates. 
     
     
         18 . A pharmaceutical formulation according to  claim 7 , wherein the particles include those with a crystalline core of D,L-valine and a coating of insulin; a crystalline core of L-glycine and a coating of antitrypsin, a crystalline core of Na glutamate and a coating of insulin; a crystalline core of L-methionine and a coating of insulin; a crystalline core of L-alanine and a coating of insulin; a crystalline core of L-valine and a coating of insulin; a crystalline core of L-histidine and a coating of insulin; a crystalline core of L-glycine and a coating of α-antitrypsin; a crystalline core of L-glutamine and a coating of albumin: a crystalline core of D,L-valine and a coating of oligonucleotides DQA-HEX; a crystalline core of D,L-valine and a coating of α1-antitrypsin with a further anti-oxidant outer coating of N-acetyl cystein; a crystalline core of D,L-valine and a coating of ovalbumin; a crystalline core of L-glutamine and a coating of ovalbumin, a crystalline core of D,L-valine and a coating of diptheria taxoid; a crystalline core of L-glutamine and a coating of diptheria taxoid; a crystalline core of D,L-valine and a coating of diptheria taxoid; a crystalline core of the L-glutamine and a coating of tetanus taxoid; a crystalline core of the D,L-valine and a coating of a mixture of diptheria taxoid and tetanus taxoid; a crystalline core of L-glutamine and a coating of a mixture of diptheria taxoid and tetanus taxoid. 
     
     
         19 . A pharmaceutical formulation for pulmonary delivery comprising microcrystals formed according to  claim 1 . 
     
     
         20 . A pharmaceutical formulation according to  claim 19 , wherein bioactive molecules for the formation of pulmonary pharmaceutical formulations are selected from any of the following: therapeutic proteins such as insulin, α1-antitrypsin, interferons; antibodies and antibody fragments and derivatives; therapeutic peptides and hormones; synthetic and natural DNA including DNA based medicines; enzymes; vaccine components; antibiotics; pain-killers; water-soluble drugs; water-sensitive drugs; lipids and surfactants; polysaccharides; or any combination or derivatives thereof. 
     
     
         21 . A pharmaceutical formulation according to  claim 19 , wherein the pulmonary formulations comprise particles with a mass median aerodynamic diameter less than about 10 microns or less than about 5 microns. 
     
     
         22 . A pharmaceutical formulation according to  claim 19 , wherein the pulmonary formulations have crystalline cores comprised of amino-acids such as valine, histidine, isoleucine, glycine or glutamine and which, for example, include: a crystalline core of valine and a coating of a therapeutic protein such as insulin; a crystalline core of histidine and a coating of an enzyme; a crystalline core of valine and a coating of an enzyme inhibitor such as α-antitrypsin; a crystalline core of valine and a coating of DNA; a crystalline core of valine and a vaccine coating; a crystalline core of glutamine and a vaccine coating; a crystalline core of glutamine and a coating of albumin. 
     
     
         23 . A parenteral formulation comprising microcrystals or suspensions of microcrystals formed according to  claim 1 . 
     
     
         24 . A sustained or controlled release pharmaceutical formulation (or a depots) comprising microcrystals or suspensions of microcrystals formed according to  claim 1 . 
     
     
         25 . A drug delivery device for inhalation comprising microcrystals formed according to  claim 1 . 
     
     
         26 . A method of determining optimum conditions for making bioactive molecule coated microcrystals comprising the steps of:
 preparing a first batch of bioactive molecule coated microcrystals according to a first set of variable parameters and quantifying at least one property of said bioactive molecule coated microcrystals;   preparing a second batch of bioactive molecule coated microcrystals by changing at least one of the variable parameters, and quantifying said at least one property in order to be able to ascertain if said at least one change has a beneficial or detrimental effect on said at least one property.   
     
     
         27 . A method of receiving a request to form bioactive molecule coated microcrystals formed according to  claim 1  comprising:
 (a) a customer defining requirements for bioactive molecule coated microcrystals including that of bioactivity, dosage, loading, size, shape and coprecipitant;   (b) tuning the coprecipitation conditions in order to obtain microcrystals as defined in part (a);   (c) refining the coprecipitation conditions to obtain microcrystals with appropriate requirements; and   (d) identifying appropriate conditions to form the required microcrystals.   
     
     
         28 . A method of providing services relating to a method of forming bioactive molecule coated microcrystals according to  claim 1 , said method comprising:
 receiving a request from a customer to form bioactive molecule coated microcrystals with particular requirements including that of size and bioactivity;   determining a method of forming said bioactive molecule coated microcrystals; and   receiving payment for providing services of said method of forming bioactive molecule coated microcrystals to the customer.